PROJECT SUMMARY: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia: it contributes to 80,000 deaths annually and affects approximately 3.4 million Americans, with a projected increase to 10 million over the next 30 to 40 years. The primary electrical therapy for termination of AF, DC cardioversion, has significant side effects including electroporation and tissue damage, in addition to risks from sedation that can result in aspiration of stomach contents, pneumonia, and other problems. Radiofrequency ablation has a success rate of only up to 60% for paroxysmal AF, but less than 30% for persistent AF. Approaches to manage AF are not all successful and improvements are needed. We propose to further study, optimize and bring closer to the clinic our developed low-energy electrical therapy for AF suppression, low-energy antifibrillation pacing (LEAP). This consists of a train of 5 electrical pulses delivered at or near the dominant frequency of the arrhythmia from two field electrodes, rather than from a point source. We have shown that LEAP has a success rate of more than 94% and uses less than 10% the energy of cardioversion. LEAP suppresses AF by virtual electrodes created at heterogeneities within the tissue, which permits overdrive or underdrive pacing of AF. We hypothesize that synchronization is the mechanism by which AF is terminated via LEAP and thus, can be applied to any animal species and be optimized to be used in humans and eventually to be used as treatment requiring very small energies. Our ex-vivo optical mapping (OM) experiments and in-vivo studies in intact dogs have demonstrated that LEAP extinguishes AF with energies as low as 0.05 J, more than ten times less than conventional cardioversion. Given these encouraging results, we plan to adopt an integrative approach to optimizing this technology for possible clinical use. (1) We will develop fast-state-of-the-art 3D physiological and structural accurate computer models of AF, validated using OM voltage data from dogs, pigs and explanted human hearts (obtained from the heart transplant program at Emory Hospital) to better understand and distinguish arrhythmias between species, structures and sizes. (2) We will iteratively perform ex- vivo AF experiments in dog, pigs and human hearts and computers simulations and in-vivo AF experiments in dogs and pigs to test our synchronization hypothesis and use it to optimize electrode configurations, pulse waveforms and pulse timing for AF suppression using the lowest energies possible (below the pain threshold), Thereby paving the way for development of implantable devices as another methods for managing AF in patients. The findings from this research will not only lead to new and improved cardioversion therapies with greater reductions in pain, but also will fundamentally advance our mechanistic understanding of AF from the combined ex vivo Langendorff perfused dog, pig and human optical mapping and basket catheter experiments and their physiologically accurate computer simulation counterparts. An additional important impact from this study, is that we will enhance resources available for the study of arrhythmias by creating extensive high time/space resolution OM voltage data sets and a near-real-time 3D simulation platform with accurate atrial electrophysiology and structures running in a web- browser environment that will be made available to other researchers and the public in general via a dedicated website.